Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

Abstract

The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

Thymus antibody-secreting cells possess an interferon gene signature and are preferentially expanded in young female mice

“…In this regard, human studies have identified ASC populations in the neonatal THY which are preserved and potentially expanded over the course of aging. 22 , 23 Histological analyses in humans have shown these cells to be located within the perivascular space (PVS) of the THY medulla 22 , 23 and recent RNA-sequencing (RNA-seq) experiments have inferred an intra-THY development of these cells. 22 From a functional standpoint, THY ASC Abs have been shown to be virally and bacterially reactive, 22 , 23 but it is unclear as to what percentages these reactivities occupy within the total THY ASC Ab repertoire.…”

Thymus Antibody-Secreting Cells Represent a Tissue Specific Population That Possess an Activated Cellular Phenotype

“…Previous work has identified the presence of ASCs in the human THY (Cordero et al, 2021; Nunez et al, 2016). Similarly, ASCs have been observed in the mouse THY (Haba and Nisonoff, 1992; Hidalgo et al, 2020) but remain to be fully characterized.…”

“…Recent studies in humans have identified ASC populations in the neonatal THY which are preserved and potentially expanded over the course of aging (Cordero et al, 2021; Nunez et al, 2016). Histological analyses in humans have shown these cells to be located within the THY perivascular space (PVS) (Cordero et al, 2021; Nunez et al, 2016) and recent RNA-sequencing (RNA-seq) experiments have inferred an intra-THY development of these cells (Cordero et al, 2021). This latter point being of particular interest as experiments using mice have shown the ability of autoreactive THY B cells to class-switch following their interactions with developing T lymphocytes (Perera et al, 2016).…”

Single-Cell Technologies for the Study of Antibody-Secreting Cells

“…Plasmablasts are an unstable ASC intermediate that require input from a survival niche to persist long term. The bone marrow has been extensively studied as an ASC niche for its role in harboring ASC following infection and immunization, however the majority of ASC are located in the gut-associated lymphoid tissue and produce IgA (6); the thymus has also recently emerged as an ASC niche (7,8). The factors involved in early-ASC homing to survival niches are not completely understood.…”